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Use of Prourokinase and Variants Thereof in Facilitated Percutaneous Coronary Intervention in Patients with Acute Myocardial Infarction

a technology of prourokinase and percutaneous coronary intervention, which is applied in the field of biological medicines, can solve the problems of high poor efficacy and safety of facilitated pci therapy, and patients who cannot receive direct pci therapy, so as to prevent hemorrhagic complications, reduce the incidence rate of reinfarction after thrombolysis, and high selectivity

Active Publication Date: 2011-09-22
BOSTON PI CARDIO INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0024]The reason for the good effect of the combination of proUK or variants thereof and PCI lies in that, proUK or variants thereof are serine proteolysis zymogens having dual characteristics of enzyme and zymogen. After entering the blood circulation intravenously, as a zymogen, proUK or variants thereof will not cause systematic plasminogen activation; and as an enzyme, proUK or variants thereof can dissolve the embolized thrombus with a high selectivity, without acting on hemostatic thrombus at wounds at tissues and organics, and thus prevent hemorrhagic complications upon thrombolytic therapy to the utmost extent. As proUK or variants thereof also have the function of inhibiting platelet aggregation, the incidence rate of reinfarction after thrombolysis may be reduced. The reinfarction rate of AMI treated with proUK or variants thereof is much lower than that of tPA, such that the opportunity of reinfarction after implanting the stent during the PCI operation is reduced, and thus the mortality is significantly reduced.

Problems solved by technology

However, due to the limitations such as the PCI equipment in the local medical institution where the patient visits, whether a skilled operator can be in position timely, and inevitable time delay during the transportation of a patient, even in American with very advanced medical services, only 4% of the patients after referral can achieve the treatment objective of receiving direct PCI for reperfusion within 90 min after the medical visit, and about 60-70% of the patients cannot receive direct PCI therapy in time[4].
However, the effectiveness and safety of the facilitated PCI by using presently approved thrombolytic drugs, such as streptokinase and TPA (including, for example, TNK, reteplase, and alteplase) are significantly poorer than those of the direct PCI[8,9], which may be related to that the TPA thrombolytic drugs may activate the coagulation system upon use and thus the incidence rate of reinfarction is high.

Method used

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  • Use of Prourokinase and Variants Thereof in Facilitated Percutaneous Coronary Intervention in Patients with Acute Myocardial Infarction

Examples

Experimental program
Comparison scheme
Effect test

embodiment 1

ProUK and Variants Thereof

[0028]ProUK was an extracted natural proUK or a recombinant human proUK, and had an amino acid sequence as shown in SEQ ID NO.1.

[0029]The variants of proUK were proteins or polypeptides with one or more amino acids replaced, deleted, or added in the amino acid sequence of proUK and having proUK activity; proteins with higher than 40% homology with the whole sequence of the natural proUK protein; or proteins or polypeptides with higher than 90% homology with the B chain sequence of the natural proUK protein.

[0030]A specific example of the variants of proUK was proUK having a lysine (Lys) at position 300 in the amino acid sequence of proUK as shown in SEQ ID NO.1 site-mutated into histidine (His).

[0031]ProUK and variants thereof can be prepared by a gene engineering method well-known in the art.

embodiment 2

In-Vivo and In-Vitro Experiments Indicate that a Specific Example of the Variants of proUK (Having a Lysine (Lys) at Position 300 in the Amino Acid Sequence of proUK as Shown in SEQ Id NO.1 Site-Mutated into Histidine (his), Lys300 →His, M5) has a Thrombolytic Activity at Least Equivalent to or Superior to that of proUK, and Thus is Applicable in Facilitated PCI Therapy

[0032](1) In-vitro Experimental Results of M5

[0033]1.1 Intrinsic Catalytic Activity Test

[0034]As for the hydrolysis of a chromophoric substrate S2444 (L-pGlu-L-Gly-Arg p-nitroanilide hydrochloride), 1.0 mol / L proUK or 100 mol / L M5 and a series of concentrations (0-2.4 mmol / L) of S2444 were co-incubated in a buffer solution (0.05 mol / L Tris-HCl, 0.10 mol / L NaCl, and 0.01% Tween 80, pH 7.4) at room temperature, the reaction rate was determined by an increment in light absorption at 410 nm, and the reaction constant was calculated through a Lineweaver-Burk plot. The results show that, the lag phase of MS is twice that of...

embodiment 3

Application of ProUK in Facilitated PCI

[0055](1) Selection Criteria

[0056]1.1 Ischemic chest pain lasting for 30 min or more, and sublingual administration of nitroglycerin being ineffective;

[0057]1.2 Sustained ischemic chest pain lasting for 12 hrs or less;

[0058]1.3 Electrocardiogram (ECG) having at least two or more ST segment elevations of 0.1 mV or more in limb lead, or two or more adjacent ST segment elevations of 0.2 mV or more in chest lead; and

[0059]1.4 Age of 85 years old or less, male or female.

[0060](2) Exclusion Criterion

[0061]2.1 Non-ST segment-elevation AMI or unstable angina pectoris;

[0062]2.2 Women during pregnant stage, breast-feed stage, and menstrual period;

[0063]2.3 Hemorrhagic stroke occurred at anytime in the past, and ischemic stroke or cerebrovascular event occurred in 1 year;

[0064]2.4 Severe progressive diseases (such as malignant tumor) or diseases with poor prognosis and making the patient to be extremely exhausted;

[0065]2.5 Active visceral hemorrhage (such...

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Abstract

In the field of biological medicines, a use of prourokinase (proUK) and variants thereof in facilitated percutaneous coronary intervention (PCI) in patients with acute myocardial infarction is provided. The use includes: within 6 hrs after a patient is afflicted with accurate myocardial infarction (AMI), firstly, performing thrombolytic therapy with proUK or variants thereof, and then, performing a PCI operation, to dredge the infarction related artery (IRA) as soon as possible, and re-establish an effective forward blood flow, such that an ischemic myocardium is reperfused. According to the present invention, the facilitated PCI for treatment of AMI with the proUK or variants thereof has an effect superior to that of direct PCI.

Description

BACKGROUND OF THE INVENTION[0001]1. Field of Invention[0002]The present invention relates to the field of biological medicines, and more particularly to a use of a plasminogen activator prourokinase (proUK) and variants thereof in facilitated percutaneous coronary intervention (PCI) in patients with accurate myocardial infarction (AMI).[0003]2. Related Art[0004]It is a most important strategy, in early-stage treatment of AMI, to dredge the infarction related artery (IRA) as soon as possible to re-establish an effective forward blood flow, such that an ischemic myocardium is reperfused.[0005]Direct PCI and intravenous thrombolytic therapy are two main methods for dredging the IRA and performing reperfusion to reduce the mortality.[0006]The optimal time for reperfusion to treat AMI is within 1 hr after the onset of the chest pain, and it is critical for reducing the mortality and the disability rate to shorten the time from the onset of the chest pain to the effective reperfusion of t...

Claims

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Application Information

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IPC IPC(8): A61K38/49A61P7/02
CPCC12N9/6424A61K38/49A61P7/02A61P9/10
Inventor LIU, JIANNING
Owner BOSTON PI CARDIO INC
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